Introduction

Inflammatory bowel disease (IBD) is a chronic inflammatory disorders of the gastrointestinal tract. Up to 30% of people with active IBD experience mood disorders such as depression. We utilizes data from the Global Burden of Diseases (GBD) 2021 to analyze the national-level burden of IBD, trends in disease incidence, and epidemiological characteristics. Our objective was also to identify the pathways associated with the interplay between IBD and depression.

Aims & Methods

Detailed information on IBD and depression was gathered from 204 countries and territories spanning 1990 to 2021, sourced from the GBD 2021. Calculations were performed for incidence rates, prevalence rates, disease-adjusted life years (DALYs), years lived with disability (YLDs) and estimated annual percentage changes (EAPCs). In addition, we assessed the Spearman's rank correlation between the incidence rates of IBD and depression and constructed an age–period–cohort model using incidence data from 1992 to 2021. We selected three GEO datasets (GSE87473, GSE92415, and GSE112366) and conducted data integration and preprocessing using the data.table and tidyverse packages in R. Differential expression analysis was performed on the batch-corrected data using the limma package. Furthermore, we curated a list of 153 depression-associated genes from published studies and executed intersection analysis with the identified DEGs. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were carried out. Finally, we use animal model and clinical sample to verify pathway expression. GSVA enrichment analysis based on the “H: hallmark gene sets” to investigate the underlying molecular biological alterations.

Results

The incidence of both IBD and depression has been increasing annually in China and globally. Over the past 30 years, the incidence of IBD in China has shown a marked upward trend, while the incidence of depression has exhibited a downward trend. The DALY and YLD rates for both IBD and depression have declined over time. A strong positive correlation between IBD and depression was observed in high-SDI regions and the United States; however, partial correlation analysis controlling for the effect of year revealed no strong linear association between the two. The APC models for IBD and depression indicated that age and period effects play a significant role in the incidence of both diseases. Using the gene expression matrix and sample metadata from 630 IBD patients of GEO database, we validated the removal of technical variation via principal component analysis (PCA). We identified 2560 upregulated and 2593 downregulated genes between IBD and healthy control groups. Intersection of these DEGs with a curated list of 153 depression-related genes revealed 25 overlapping core genes. Then, GO and KEGG enrichment and GSVA analyses highlighted α-Linolenic acid metabolism as a potential key pathway in the IBD-depression comorbidity.Finally, both animal model and clinical sample comfired the expression levels associated with the α-Linolenic acid metabolism pathway.

Conclusion

Although significant progress has been made in the diagnosis and treatment of IBD in China, issues such as delayed identification of depressive symptoms may still persist. Notably, the relative risk of depression has shown an upward trend among individuals born after 2000. Our study discovered α-Linolenic acid metabolism may constitute a critical biological link between IBD and depression, providing novel insights for investigating the shared pathophysiological mechanisms underlying this comorbidity.

Introduction

Intestinal barrier integrity is emerging as a key therapeutic target in inflammatory bowel disease (IBD). Advanced endoscopic imaging techniques, including ultra-high magnification endocytoscopy (ECS) and probe-based confocal laser endomicroscopy (pCLE), enable real-time, in vivo structural and functional intestinal barrier assessment. Raman Spectroscopy (RS) can add a molecular dimension through vibrational fingerprinting of barrier-associated metabolites in biological samples.¹

Aims & Methods

This study explores the potential of RS integration with advanced endoscopy to characterise the intestinal barriers in IBD, targeting on tryptophan-derived metabolites and carbohydrates. A total of 46 IBD patients [25 Crohn’s disease (CD) and 21 ulcerative colitis (UC)] and 7 healthy controls (HC) undergoing endoscopic assessment or surveillance were prospectively enrolled from two academic centres. ECS or pCLE were used to evaluate epithelial and vascular barrier integrity. Barrier healing was defined as ECS score ≤ 1 or pCLE score ≤ 4, with preserved villi/crypt architecture, normal vasculature, and also absence of fluorescein leakage for pCLE. Advanced endoscopy-guided biopsies were collected from representative bowel segments. Mucosal healing (MH) was assessed by experienced pathologists using Nancy’s Histological Index ≤1. Epithelial (Claudin-2 and ZO-1) and vascular (PV-1 and CD-31) barrier markers were analysed through confocal microscopy, and their expression was automatically quantified using QuPath. Micro-RS was applied to tissue samples and matched sera to measure key tryptophan metabolites (kynurenine, indolepropionic acid, and melatonin) and carbohydrates.^2,3 Six-month major adverse outcomes (MAOs) were recorded. Group differences in Raman spectra were analysed with the Mann-Whitney test; correlations were assessed via Pearson’s test.

Results

Among patients undergoing ECS, barrier healing was observed in 10/22 (45%) colonic and 6/9 (67%) ileal cases. pCLE-based assessment revealed healing features in 5/16 (31%) colonic and 2/15 (13%) ileal evaluations. Raman spectral analysis showed a significant (p<0.05) reduction in tryptophan metabolites and carbohydrate-associated peaks in IBD tissues and sera compared to HC, especially in inflamed patients. When stratified by advanced endoscopy-identified barrier integrity, tryptophan metabolites -known barrier modulators-, and carbohydrates -likely reflecting mucin barrier layer- were markedly reduced (p<0.05) in patients with impaired barrier function. Notably, tryptophan derivatives positively correlated with Claudin-2 and ZO-1 in UC (r>0.4), and with PV-1 in CD (r>0.5). Similarly, carbohydrates correlated positively with Claudin-2 in UC (r=0.4) and negatively with CD-31 in CD (r=-0.4). Lower levels of indolepropionic acid and carbohydrates correlated with worse short-term MAOs (r<-0.4).

Conclusion

The integration of RS with advanced endoscopic images offers a novel, multi-layered approach to assess intestinal barrier integrity in IBD. RS can identify novel non-invasive biomarkers of mucosal and barrier healing, with potential real time applications for monitoring disease activity and predicting therapeutic outcome. Tryptophan metabolites may serve as a predictive biomarker of barrier healing paving the way toward personalised, barrier-targeted therapies.

References

1 Smith SCL, Banbury C, Zardo D, et al. PLoS One 2021; 16: e0252210.
2 Michaudel C, Danne C, Agus A, et al. Gut 2023; 72: 1296–307.
3 Arras W, Breugelmans T, Oosterlinck B, et al. J Crohns Colitis 2025; 19.

Introduction

Mirikizumab is an anti-IL-23p19 monoclonal antibody, a key mediator in the pathogenesis of inflammatory bowel diseases. We evaluated the induction efficacy and safety of mirikizumab in the LUCENT-1 (NCT03518086) Chinese subpopulation.

Aims & Methods

In this Phase 3, multi-center, randomized, parallel-arm, double-blind, placebo-controlled trial, conventional-failed or biologic/tofacitinib-failed Chinese adult patients (N=184) with moderately to severely active ulcerative colitis (UC, Modified Mayo Score 4-9, endoscopic subscore ≧2) were randomized in a 3:1 ratio to 300 mg mirikizumab (intravenous) or placebo every 4 weeks for 12 weeks. Randomization was stratified by biologic/tofacitinib failure status, baseline corticosteroid use and baseline disease activity (Modified Mayo Score). The primary objective was to test the hypothesis that mirikizumab was superior to placebo in inducing clinical remission at Week 12 (W12). Key secondary endpoints included alternate clinical remission, clinical response, clinical response in biologic-failed patients, symptomatic remission, endoscopic remission, histologic-endoscopic mucosal and bowel-movement urgency improvement. Analyses in Chinese subpopulation were descriptive. Missing data was imputed as non-responders for the categorical endpoints. Bowel urgency change from baseline data was reported based on Mixed Model Repeated Measured.

Results

Baseline characteristics were balanced across groups. A greater proportion of mirikizumab-treated patients achieved clinical remission (18.6% vs. 7.0%; Δ=11.5 [95%CI: 1.7, 21.3]) and alternate clinical remission at W12 (21.4% vs. 7.0%; Δ=14.3 [95%CI: 4.4, 24.2]). Mirikizumab also improved key secondary endpoints at W12. The frequencies of treatment-emergent adverse events were similar between groups (mirikizumab [60.0%] vs. placebo [62.8%]). There were fewer serious adverse events (10 [7.1%] vs. 7 [16.3%]) and discontinuations due to adverse events (2 [1.4%] vs. 3 [7.0%]) in mirikizumab-treated patients compared to placebo. There was 1 adenocarcinoma of colon (mirikizumab group) and no deaths during the treatment period.

Conclusion

Efficacy and safety profiles were consistent with LUCENT-1 overall population, supporting benefits of mirikizumab treatment in the Chinese UC patients.

Disclosure

No conflict of interest to disclose

Introduction

Janus kinase inhibitors (JAKi) exhibit distinct performance characteristics versus monoclonal antibody (mABs) biological agents in the management of ulcerative colitis (UC). There is a lack of direct comparative effectiveness data of JAKi small molecules versus mABs in the real world.

Aims & Methods

In the absence of direct head-to-head comparisons, we determined the persistence of tofacitinib (TOF) versus vedolizumab and tumour necrosis factor inhibitor (TNFi) mABs in advanced therapy (AT)-naïve and AT-exposed real-world UC subjects from a population-based prospective registry.

The Persistence Australian National IBD Cohort (PANIC5) registry collected AT prescribing data for the entire Australian population up until Dec 2021. In Australia, all advanced therapies for IBD are prescribed without a hierarchical order in subjects with moderate-severe UC refractory to conventional therapies, irrespective of occupation and insurance status. Treatment is provided indefinitely in those that enter into clinical remission. Non-persistence was defined as failure to continue AT prescriptions for >6-months. Propensity score matching (PSM) statistically controlled for baseline selection biases. Kaplan-Meier survival curves were generated for AT persistence and compared using the log-rank test. Cox proportional hazards regression models were employed to calculate hazard ratios (HR) and 95% confidence intervals (CI). P<0.05 was deemed statistically significant (SPSS, USA).

Results

A total of 9,671 consecutive UC patients were recruited (53% male, 23,348 patient-years of follow up). The cohort comprised 14,772 treatment lines: 6,044 infliximab (IFX), 1,981 adalimumab (ADA), 5,467 vedolizumab (VED), 750 golimumab (GOL) and 530 tofacitinib (TOF). TOF exhibited superior persistence versus IFX (HR: 1.88, 95%CI: 1.34-2.63, P<0.001), ADA (HR: 2.10, 95%CI: 1.49-2.94, P<0.001) and GOL (HR: 2.20, 95%CI: 1.55-3.11, P<0.001) but not versus VED (HR: 1.28, 95%CI: 0.92-1.80, P=0.14). Following PSM, TOF was not significantly higher in persistence compared to mABs among AT-naïve subjects (all P>0.05). However, TOF showed superior persistence compared to all mABs among AT-exposed (all P<0.001). The persistence of TOF (P=0.77) did not significantly decline moving from AT-naive- to AT-exposed treatment status, unlike for TNFi (-8 months) and VED (-19 months, both P<0.001). PSM-multivariate Cox regression showed predictors of higher persistence to be use of TOF, AT-naïve status, use of immunomodulator. Rankings of persistence of ATs are presented for AT-naïve- and AT-exposed UC subjects (Table).

Conclusion

This is the first real-world study comparing treatment effectiveness using a national universal insurance persistence dataset. It found that tofacitinib had significantly greater persistence than biological agents in patients with ulcerative colitis who had previously received advanced therapy. Unlike monoclonal antibodies, tofacitinib did not show a decline in persistence after exposure to advanced therapy. Given these findings, JAK inhibitors like tofacitinib should be strongly considered for patients switching advanced therapies in ulcerative colitis.

Disclosure

RL advisory board: AbbVie, Aspen, BMS, Celgene, Celltrion, Chiesi, Ferring, Glutagen, Hospira, Janssen, Lilly, MSD, Novartis, Pfizer, Prometheus Biosciences, Takeda; research grants: Joanna Tiddy USYD, McCusker Charitable Foundation, Celltrion, Shire, Janssen, Takeda, Gastroenterological Society of Australia, NHMRC, Gutsy Group, Pfizer, MRFF

Introduction

Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are complex conditions characterized by significant clinical, immunological, molecular, genetic, and microbiological heterogeneity. Current therapeutic strategies, particularly biologics and Janus kinase (JAK) inhibitors, are effective for inducing clinical remission and controlling inflammation. However, one-third of patients fail to respond to these treatments, highlighting the need for predictive biomarkers to better tailor therapy and improve outcomes.

Aims & Methods

In this study, we conducted a multi-omic approach, integrating transcriptomics, proteomics, metabolomics, and metagenomics to identify biomarkers of treatment response in IBD. A cohort of 57 active CD and 70 active UC patients was analyzed before and after 14 weeks of treatment with anti-TNF, ustekinumab, vedolizumab, or tofacitinib. Response was evaluated using endoscopic criteria, categorizing patients as responders or non-responders. Biological samples [serum, urine, serum extracellular vesicles (EVs), intestinal biopsies, and stool] were analysed using RNA sequencing, liquid chromatography-mass spectrometry, nuclear magnetic resonance, and 16S rRNA gene sequencing to assess molecular and microbial profiles.

Results

Our results identified multiple mRNAs, proteins and metabolites associated with treatment response. Gene expression analysis in intestinal tissue showed significant differences between UC patients responders and non-responders to vedolizumab. Proteomic analysis of serum EVs and intestinal tissue samples revealed differentially expressed proteins between different study groups. Metabolomic analysis identified deregulation of 24 serum lipoproteins from CD responders to ustekinumab compared to non-responders. Pathway analysis highlighted significant enrichment in ketone and butyrate metabolism, mitochondrial electron transport chain activity, carnitine synthesis, and fatty acid oxidation pathways. Metagenomic analysis revealed microbial differences in UC patients responders to anti-TNF therapy compared to non-responders.

Conclusion

This multi-omics analysis uncovers promising biomarkers that could serve as predictive indicators of therapeutic response to biologics and JAK inhibitors. Nevertheless, further studies are crucial to confirm these findings and evaluate their clinical relevance in identifying patients most likely to respond to tailored therapeutic interventions. One of the challenges is integrating results from different omics approaches to create a more holistic understanding of the disease, potentially opening doors for more precise/early detection through multipanel biomarkers.